Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A.

Bark-stripping Behavior of Formosan Sambar () at Tataka, Yushan National Park in Taiwan.

The bark-stripping behavior of Formosan sambar, , has become conspicuous in recent years in the Tataka area of Yushan National Park in Taiwan and a cause for concern to visitors and ecologists. We conducted a monthly survey of 537 tagged trees of 21 species and monitored the abundance of sambar using camera traps from October 2018 to January 2021, aiming to interpret possible causes of the bark-stripping behavior in Tataka. We also used a generalized linear model to evaluate factors that may affect the probability of a tree having its bark stripped.

Maturation and circuit integration of transplanted human cortical organoids.

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits.

Engineering brain assembloids to interrogate human neural circuits.

The development of neural circuits involves wiring of neurons locally following their generation and migration, as well as establishing long-distance connections between brain regions. Studying these developmental processes in the human nervous system remains difficult because of limited access to tissue that can be maintained as functional over time in vitro. We have previously developed a method to convert human pluripotent stem cells into brain region-specific organoids that can be fused and integrated to form assembloids and study neuronal migration.

Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome.

Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca1.2.

Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells.

Cortico-striatal projections are critical components of forebrain circuitry that regulate motivated behaviors. To enable the study of the human cortico-striatal pathway and how its dysfunction leads to neuropsychiatric disease, we developed a method to convert human pluripotent stem cells into region-specific brain organoids that resemble the developing human striatum and include electrically active medium spiny neurons. We then assembled these organoids with cerebral cortical organoids in three-dimensional cultures to form cortico-striatal assembloids.

Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids.

Retinoid X Receptor α Regulates DHA-Dependent Spinogenesis and Functional Synapse Formation In Vivo.

Coordinated intracellular and extracellular signaling is critical to synapse development and functional neural circuit wiring. Here, we report that unesterified docosahexaenoic acid (DHA) regulates functional synapse formation in vivo via retinoid X receptor α (Rxra) signaling. Using Rxra conditional knockout (cKO) mice and virus-mediated transient gene expression, we show that endogenous Rxra plays important roles in regulating spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons.

A Critical Role of Presynaptic Cadherin/Catenin/p140Cap Complexes in Stabilizing Spines and Functional Synapses in the Neocortex.

The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized β-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects.

CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development.

Studying the early function of essential genes is an important and challenging problem in developmental biology. Here, we established a method for rapidly inducing CRISPR-Cas9-mediated mutations in one blastomere of two-cell stage embryos, termed 2-cell embryo-CRISPR-Cas9 injection (2CC), to study the in vivo function of essential (or unknown) genes in founder chimeric mice. By injecting both Cre mRNA and CRISPR-Cas9 targeting the gene of interest into fluorescent reporter mice, the 2CC method can trace both wild-type and mutant cells at different developmental stages, offering internal control for phenotypic analyses of mutant cells.

[Treatment of the postoperative infection of limbs fracture after internal fixation with vacuum sealing drainage (VSD) combined with continual irrigation].

Objective: To explore the clinical effects of VSD combined with continual irrigation in treating the infection of limbs fracture after internal fixation.

Methods: From March 2010 to June 2015, 10 patients with infection of limbs fracture after internal fixation were treated with VSD combined with continual irrigation. There were 7 males and 3 females, aged from 11 to 58 years with an average of 34.

[The Effect in Extraction of Different Ratio of Dahuang-Taoren for Ten Kinds of Chemical Constituents from Rhizoma Rhei].

Objective: To investigate the effect of Dahuang-Taoren with different proportion of extraction amount changes of ten kinds of chemical constituents in Rhizoma Rhei.

Methods: Uniform method to set different ratio( 1∶ 5,2∶ 5,2∶ 3,1∶ 1,3∶ 2,5∶ 2,5∶ 1),and set the control group ( Dahuang-Taoren( 1 ∶ 0). HPLC was used to determine the content of ten constituents as gallic acid,( +)-catechin,sennoside B,anthraquinones( aloe-emodin,rhein,emodin,chrysophanol,physcion,chrysophanol-1-O-glucoside,emodin major grape glycoside) in different ratio of drug.

Postsynaptic spiking homeostatically induces cell-autonomous regulation of inhibitory inputs via retrograde signaling.

Developing neural circuits face the dual challenge of growing in an activity-induced fashion and maintaining stability through homeostatic mechanisms. Compared to our understanding of homeostatic regulation of excitatory synapses, relatively little is known about the mechanism mediating homeostatic plasticity of inhibitory synapses, especially that following activity elevation. Here, we found that elevating neuronal activity in cultured hippocampal neurons for 4 h significantly increased the frequency and amplitude of mIPSCs, before detectable change at excitatory synapses.

[Experimental study of gene therapy with human vascular endothelial growth factor-c in lymphedema].

Objective: To study the efficacy of gene therapy with human vascular endothelial growth factor-c (VEGF-C) on obstructive lymphedema.

Methods: Two animal models of lymphedema were created: one in the right hind limb of adult New Zealand white rabbits and the other in SD mouse tail. Each model was randomly divided into two groups to receive intradermal injection of either VEGF-C gene (experimental group), or saline(control group).

Prospective study in 142 cases of hepatitis C virus infection.

Aim: There is limited information on the natural history of HCV infection in China. We investigated the outcome of HCV infection after nine-year follow-up and the risk factors in blood donors in China in order to provide the foundation for prevention and therapy.

Methods: A total of 172 cases of HCV infection with anti-HCV positive and ALT abnormality were enrolled in the archives when was screened blood in Hebei Province in 1993.

Association of interleukin-12 p40 gene 3'-untranslated region polymorphism and outcome of HCV infection.

Aim: To investigate the effect of interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism on the outcome of HCV infection.

Methods: A total of 133 patients who had been infected with HCV for 12-25 (18.2+/-3.

[Nine-year follow-up of hepatitis C virus infection in a rural area of Hebei province, China].

Objective: To investigate natural history of hepatitis C virus infection and related factors among plasma donors in China.

Methods: 172 plasma donors in a rural area of Hebei province had been diagnosed as HCV infection in 1993. No antiviral treatment was applied to them during the period of infection.

Pathogenicity of GB virus C on virus hepatitis and hemodialysis patients.

Aim: To determine the pathogenicity of GB virus C (GBV-C) on liver and the effects of its co-infection on the clinical features and prognosis of patients with hepatitis B and C.

Methods: Cross-sectional study was carried out in 413 patients with acute, chronic hepatitis B or liver cirrhosis, and in 67 hemodialysis patients. A 20-month prospective cohort study was carried out in 95 hepatitis B and 80 hepatitis C patients.